Orthosteric- and allosteric-induced ligand-directed trafficking at GPCRs.
Summary of "Orthosteric- and allosteric-induced ligand-directed trafficking at GPCRs."
Many orthosteric agonists differentially activate downstream effectors of GPCRs. Such defined induction of signaling has strongly supported the hypothesis termed 'ligand-directed trafficking of receptor signaling' (LDTRS). More recently, subtype-selective GPCR activators, such as allosteric agonists and positive allosteric modulators, have also exhibited the capacity to activate specific signaling pathways. Based on this finding, it may be possible to achieve ligand-specific receptor active states that optimize the biological responses specific to GPCRs. This review discusses recent studies in which both orthosteric and allosteric compounds have been demonstrated to induce LDTRS.
Affiliation
Vanderbilt University, Department of Chemistry, 7330 Stevenson Center, Station B 351822, Nashville, TN 37235, USA. craig.lindsley@vanderbilt.edu.
Journal Details
This article was published in the following journal.
Name: Current opinion in drug discovery & development
ISSN: 2040-3437
Pages: 587-94
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20812150
- DOI: http://dx.doi.org/
Medical and Biotech [MESH] Definitions
Adp-ribosylation Factors
MONOMERIC GTP-BINDING PROTEINS that were initially recognized as allosteric activators of the MONO(ADP-RIBOSE) TRANSFERASE of the CHOLERA TOXIN catalytic subunit. They are involved in vesicle trafficking and activation of PHOSPHOLIPASE D. This enzyme was formerly listed as EC 3.6.1.47
Allosteric Regulation
The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES.
Tnf-related Apoptosis-inducing Ligand
A transmembrane-protein belonging to the TNF family of intercellular signaling proteins. It is a widely expressed ligand that activates APOPTOSIS by binding to TNF-RELATED APOPTOSIS-INDUCING LIGAND RECEPTORS. The membrane-bound form of the protein can be cleaved by specific CYSTEINE ENDOPEPTIDASES to form a soluble ligand form.
Intercellular Adhesion Molecule-1
A cell-surface ligand involved in leukocyte adhesion and inflammation. Its production is induced by gamma-interferon and it is required for neutrophil migration into inflamed tissue.
Hyperthermia, Induced
Abnormally high temperature intentionally induced in living things regionally or whole body. It is most often induced by radiation (heat waves, infra-red), ultrasound, or drugs.
PubMed Articles
"Molecular Switches" on mGluR Allosteric Ligands That Modulate Modes of Pharmacology.
G-Protein-coupled receptors (GPCRs) represent the largest class of drug targets, accounting for more than 40% of marketed drugs; however, discovery efforts for many GPCRs have failed to provide viable...
Allosteric Modulation of G Protein-Coupled Receptors: A Pharmacological Perspective.
G protein-coupled receptor (GPCR)-based drug discovery has traditionally focused on targeting the orthosteric site for the endogenous agonist. However, many GPCRs possess allosteric sites that offer e...
Cell-membrane-spanning G protein coupled receptors (GPCRs) belong to the most important therapeutic target structures. Endogenous transmitters bind from the outer side of the membrane to the "orthos...
Regulation of G protein-coupled receptors by allosteric ligands.
Topographically distinct, druggable, allosteric sites may be present on all G protein-coupled receptors (GPCRs). As such, targeting these sites with synthetic small molecules offers an attractive appr...
The cannabinoid CB(1) receptor is a class A G protein-coupled receptor (GPCR) that is the most widely expressed GPCR in the brain. Many GPCRs contain allosteric binding sites for endogenous and/or syn...
Clinical Trials
The purpose of this study is to perform an evaluation of a trauma-focused short-term intervention (Narrative Exposure Therapy; Schauer, M., Neuner, F. & Elbert, T.) on a variety of clinica...
Biological Therapy in Treating Patients With Metastatic Melanoma or Metastatic Kidney Cancer
RATIONALE: Biological therapies such as flt3L and CD40-ligand use different ways to stimulate the immune system and stop cancer cells from growing. Biological therapy may be an effective t...
Goal-Directed Afterload Reduction in Acute Congestive Cardiac Decompensation Study
The purpose of this study is to determine whether an early goal-directed decrement of preload and afterload with a target systolic blood pressure of 90-110 mmHg by aggressive vasodilatatio...
Stachybotrys Induced Hemorrhage in the Developing Lung
The majority of the workscope of this project is focussed on an infant animal model of toxigenic mold induced pulmonary hemorrhage. Clinically related studies are directed only to the des...
Prevention of Chemotherapy-Induced Cardiotoxicity in High-Risk Patients
In cancer patients, the increase of troponin I soon after chemotherapy is a strong predictor of left ventricular dysfunction and poor cardiologic outcome. This information provides a ratio...
